title: Overexpression of 5-lipoxygenase in colon polyps and cancer and the effect of 5-LOX inhibitors in vitro and in a murine model.
abstract: OBJECTIVE
  Arachidonic acid metabolism via the cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) pathways modulates cell growth and apoptosis. Many studies have examined the effects of COX inhibitors on human colorectal cancer, but the role of 5-LOX in colonic cancer development has not been well studied. The purpose of this study was to evaluate the expression of 5-LOX in colonic polyps and cancer and the effect of 5-LOX inhibition on colon cancer cell proliferation.
  
  
  METHODS
  Colonic polyps, cancer, and normal mucosa were evaluated for 5-LOX expression by immunohistochemistry. Reverse transcription-PCR was used to establish 5-LOX expression in colon cancer cells. Thymidine incorporation and cell counts were used to determine the effect of the nonspecific LOX inhibitor Nordihydroguaiaretic Acid and the 5-LOX inhibitor Rev5901 on DNA synthesis. A heterotopic xenograft model in athymic mice using HT29 and LoVo human colon cancer cells was used to evaluate the effect of the 5-LOX inhibitor zileuton on tumor growth.
  
  
  RESULTS
  5-LOX is overexpressed in adenomatous polyps and cancer compared with that of normal colonic mucosa. LOX inhibition and 5-LOX inhibition decreased DNA synthesis in a concentration- and time-dependent manner in the Lovo cell line (P < 0.05). Inhibition of 5-LOX in an in vivo colon cancer xenograft model inhibited tumor growth compared with that of controls (P < 0.05).
  
  
  CONCLUSIONS
  This study showed that 5-LOX is up-regulated in adenomatous colon polyps and cancer compared with normal colonic mucosa. The blockade of 5-LOX inhibits colon cancer cell proliferation both in vitro and in vivo and may prove a beneficial chemopreventive therapy in colon cancer.
authors.affiliation: Department of Surgery and Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
authors.forename: Laleh G
authors.initials: LG
authors.lastname: Melstrom
authors.forename: David J
authors.initials: DJ
authors.lastname: Bentrem
authors.forename: Mohammad R
authors.initials: MR
authors.lastname: Salabat
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Kennedy
authors.forename: Xian-Zhong
authors.initials: XZ
authors.lastname: Ding
authors.forename: Matthew
authors.initials: M
authors.lastname: Strouch
authors.forename: Sambasiva M
authors.initials: SM
authors.lastname: Rao
authors.forename: Richard C
authors.initials: RC
authors.lastname: Witt
authors.forename: Charles A
authors.initials: CA
authors.lastname: Ternent
authors.forename: Mark S
authors.initials: MS
authors.lastname: Talamonti
authors.forename: Richard H
authors.initials: RH
authors.lastname: Bell
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Adrian
mesh_terms: D000236:Adenoma / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D003111:Colonic Polyps / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D066298:In Vitro Techniques; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D009637:Masoprocol / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013936:Thymidine / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D016859:Lipoxygenase Inhibitors; D012333:RNA, Messenger; D009637:Masoprocol; D001094:Arachidonate 5-Lipoxygenase; D013936:Thymidine